Welcome to PracticeUpdate! We hope you are enjoying access to a selection of our top-read and most recent articles. Please register today for a free account and gain full access to all of our expert-selected content.
Already Have An Account? Log in Now
Mechanisms of Weight Loss–Induced Remission in People With Prediabetes
TAKE-HOME MESSAGE
-
This post hoc analysis of the Prediabetes Lifestyle Intervention Study investigated the mechanisms of weight loss–induced remission in people with prediabetes. Visceral adipose tissue content decreased and insulin sensitivity improved significantly in patients who had a resolution of prediabetes compared with non-responders. BMI reduction was comparable between the responder and non-responder groups. The risk of developing type 2 diabetes was 73% lower in responders than in non-responders in the 2 years after the intervention ended.
- Resolution of prediabetes was characterised by an improvement in insulin sensitivity and reduced visceral adipose tissue content in patients with prediabetes in contrast to patients with type 2 diabetes, and there was a significant reduction in the risk of developing type 2 diabetes in patients who responded to the intervention.
abstract
This abstract is available on the publisher's site.
Access this abstract now Full Text Available for ClinicalKey SubscribersBACKGROUND
Remission of type 2 diabetes can occur as a result of weight loss and is characterised by liver fat and pancreas fat reduction and recovered insulin secretion. In this analysis, we aimed to investigate the mechanisms of weight loss- induced remission in people with prediabetes.
METHODS
In this prespecified post-hoc analysis, weight loss-induced resolution of prediabetes in the randomised, controlled, multicentre Prediabetes Lifestyle Intervention Study (PLIS) was assessed, and the results were validated against participants from the Diabetes Prevention Program (DPP) study. For PLIS, between March 1, 2012, and Aug 31, 2016, participants were recruited from eight clinical study centres (including seven university hospitals) in Germany and randomly assigned to receive either a control intervention, a standard lifestyle intervention (ie, DPP-based intervention), or an intensified lifestyle intervention for 12 months. For DPP, participants were recruited from 23 clinical study centres in the USA between July 31, 1996, and May 18, 1999, and randomly assigned to receive either a standard lifestyle intervention, metformin, or placebo. In both PLIS and DPP, only participants who were randomly assigned to receive lifestyle intervention or placebo and who lost at least 5% of their bodyweight were included in this analysis. Responders were defined as people who returned to normal fasting plasma glucose (FPG; <5·6 mmol/L), normal glucose tolerance (<7·8 mmol/L), and HbA1c less than 39 mmol/mol after 12 months of lifestyle intervention or placebo or control intervention. Non-responders were defined as people who had FPG, 2 h glucose, or HbA1c more than these thresholds. The main outcomes for this analysis were insulin sensitivity, insulin secretion, visceral adipose tissue (VAT), and intrahepatic lipid content (IHL) and were evaluated via linear mixed models.
FINDINGS
Of 1160 participants recruited to PLIS, 298 (25·7%) had weight loss of 5% or more of their bodyweight at baseline. 128 (43%) of 298 participants were responders and 170 (57%) were non-responders. Responders were younger than non-responders (mean age 55·6 years [SD 9·9] vs 60·4 years [8·6]; p<0·0001). The DPP validation cohort included 683 participants who lost at least 5% of their bodyweight at baseline. Of these, 132 (19%) were responders and 551 (81%) were non-responders. In PLIS, BMI reduction was similar between responders and non-responders (responders mean at baseline 32·4 kg/m2 [SD 5·6] to mean at 12 months 29·0 kg/m2 [4·9] vs non-responders 32·1 kg/m2 [5·9] to 29·2 kg/m2 [5·4]; p=0·86). However, whole-body insulin sensitivity increased more in responders than in non-responders (mean at baseline 291 mL/[min × m2], SD 60 to mean at 12 months 378 mL/[min × m2], 56 vs 278 mL/[min × m2], 62, to 323 mL/[min × m2], 66; p<0·0001), whereas insulin secretion did not differ within groups over time or between groups (responders mean at baseline 175 pmol/mmol [SD 64] to mean at 12 months 163·7 pmol/mmol [60·6] vs non-responders 158·0 pmol/mmol [55·6] to 154·1 pmol/mmol [56·2]; p=0·46). IHL decreased in both groups, without a difference between groups (responders mean at baseline 10·1% [SD 8·7] to mean at 12 months 3·5% [3·9] vs non-responders 10·3% [8·1] to 4·2% [4·2]; p=0·34); however, VAT decreased more in responders than in non-responders (mean at baseline 6·2 L [SD 2·9] to mean at 12 months 4·1 L [2·3] vs 5·7 L [2·3] to 4·5 L [2·2]; p=0·0003). Responders had a 73% lower risk of developing type 2 diabetes than non-responders in the 2 years after the intervention ended.
INTERPRETATION
By contrast to remission of type 2 diabetes, resolution of prediabetes was characterised by an improvement in insulin sensitivity and reduced VAT. Because return to normal glucose regulation (NGR) prevents development of type 2 diabetes, we propose the concept of remission of prediabetes in analogy to type 2 diabetes. We suggest that remission of prediabetes should be the primary therapeutic aim in individuals with prediabetes.
FUNDING
German Federal Ministry for Education and Research via the German Center for Diabetes Research; the Ministry of Science, Research and the Arts Baden-Württemberg; the Helmholtz Association and Helmholtz Munich; the Cluster of Excellence Controlling Microbes to Fight Infections; and the German Research Foundation.
Additional Info
Disclosure statements are available on the authors' profiles:
Mechanisms of weight loss-induced remission in people with prediabetes: a post-hoc analysis of the randomised, controlled, multicentre Prediabetes Lifestyle Intervention Study (PLIS)
Lancet Diabetes Endocrinol 2023 Nov 01;11(11)798-810, A Sandforth, RJ von Schwartzenberg, EV Arreola, RL Hanson, G Sancar, S Katzenstein, K Lange, H Preißl, SI Dreher, C Weigert, R Wagner, K Kantartzis, J Machann, F Schick, R Lehmann, A Peter, N Katsouli, V Ntziachristos, C Dannecker, L Fritsche, N Perakakis, M Heni, PP Nawroth, S Kopf, AFH Pfeiffer, S Kabisch, M Stumvoll, PEH Schwarz, H Hauner, A Lechner, J Seissler, I Yurchenko, A Icks, M Solimena, HU Häring, J Szendroedi, A Schürmann, MH de Angelis, M Blüher, M Roden, SR Bornstein, N Stefan, A Fritsche, AL BirkenfeldFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
Reversing prediabetes is easier than reversing type 2 diabetes mellitus
The best way to reverse type 2 diabetes is to reverse prediabetes.
The Prediabetes Lifestyle Intervention Study compared responders with non-responders for reversing prediabetes in Germany. Responders were younger and lost more visceral, waistline fat and had more improvement in insulin sensitivity compared with non-responders. Responders had a 73% lower risk of type 2 diabetes 2 years after the lifestyle program.
The lifestyle program included more regular exercise, which increases the number of GLUT-4 glucose transporters that bring glucose into muscles, improving insulin sensitivity. The best way to increase the number of these important glucose transporters is to use the muscles more.
The older one gets, the longer beta-cells are subject to inflammation and insulin resistance. This makes it harder to put the disease into remission.
The take-home message of this study is to prevent prediabetes as early as possible toward an HbA1c of 5.7 or less. This is much easier than reversing type 2 diabetes to an Hb A1c of 6.5 or less.
In this paper by Sandforth et al, the authors performed a post hoc analysis of the Prediabetes Lifestyle Intervention Study (PLIS) to examine the mechanisms via which weight loss induces remission (normal HbA1c, FPG, and 2-hour glucose according to ADA criteria) in people with prediabetes. The authors concluded that “resolution of prediabetes (with >5% weight loss) was characterized by an improvement in insulin sensitivity and reduced visceral adipose tissue”, whereas weight-loss “induced remission of type 2 diabetes (based on the DIRECT study) was driven by an improvement in insulin secretion (and) not in insulin resistance”. The results were validated by comparing them to the results of the Diabetes Prevention Program (DPP). This paper makes a number of interesting, if not controversial, points.
First, the study involved prediabetic subjects who lost more than 5% of their body weight. This amounted to only 25.7% (298/1160) of participants in PLIS. The lifestyle intervention in PLIS was designed to be more intensive than that in the DPP, which already was very intensive. This underscores the difficulty in achieving substantial weight loss (>5%) with lifestyle intervention alone.
Second, only 43% (128/298) of weight loss responders returned to normal glucose regulation (NGR), while even fewer participants (19%; 132/693) in the DPP returned to NGR. This emphasizes the difficulty in achieving “remission” to NGR with weight loss alone. This is of considerable importance, since the 2-year follow-up of PLIS demonstrated that the risk of developing diabetes was reduced in subjects who achieved NGR, whereas long-term follow-up of subjects who reverted to NGT at anytime in the DPP prevented type 2 diabetes and microvascular complications.
Third, the authors’ conclusion that weight loss–induced improvement in insulin sensitivity, not increased β-cell function, is responsible for the reversion to NGR in prediabetic subjects can be questioned. The adaptation (equivalent to the disposition) index tended to increase in both groups, particularly in the responder group (Figure 2J; P-value not provided). Moreover, the p value for the weight loss–induced change in the Adaptation Index between responders versus nonresponders was 0.062. Are we really to believe that a p value of 0.062 is different from P value of .05, and that this “nonsignificant” improvement in β-cell function can be excluded as a contributing mechanism to the return to NGR? Further, there was a major mismatch in the disposition index at baseline between the responder versus nonresponder groups, being much greater in the responder group (765 vs 566; P < .0002). This could easily explain why the rise in disposition index in the responder group did not quite reach statistical significance (P = .062). Of note, the absolute value for the disposition index at study end (month 12) was much higher and significantly greater (based upon inspection of Figure 2J in the responder group). It could be argued that the absolute value for the disposition index is more relevant than the change in disposition index. Lastly, it should be noted that surrogate measures of insulin sensitivity and secretion derived from the OGTT were used in the present study, and more precise measures derived from the euglycemic insulin and hyperglycemic clamps may have provided different results, especially with respect to the difference in the disposition index between responder and nonresponder groups.
The authors obtained blood samples at 0, 30, 60, 90, 120 minutes. Why wasn’t the adaptation (disposition) index from 0 to 120 minutes calculated? Many previous studies have demonstrated that the disposition index from 0 to 120 minutes provides informative insights about the change in β-cell function in response to a variety of interventions.
Fourth, one must be careful about extrapolating results concerning the mechanism(s) about how weight loss causes reversion of prediabetes to NGR to the mechanisms involved in the reversion of prediabetes to NGT brought about by medications. Thus, multiple studies, including ACT NOW have shown that pioglitazone markedly enhances both β-cell function and insulin sensitivity.1 If improved insulin sensitivity is the major mechanism involved in reversion of prediabetes to NGT in PLIS with weight loss, then one could argue that combination therapy with pioglitazone, the only true insulin sensitizer, plus weight loss would be the ideal intervention for the treatment of prediabetes.
Fifth, the present results suggest that decreased visceral fat, not decreased hepatic fat, is related to the reversion of prediabetes to NGR, although correlations do not prove causality. This provides further support for a role for visceral fat in the pathogenesis of insulin resistance in prediabetes and type 2 diabetes.
Sixth, unlike many previous studies that have found correlations between insulin resistance and TNF-α, INF-γ, and IL-6, no weight loss–induced changes in these inflammatory cytokines were observed in the present study. Rather, TNF-β and its downstream mediators, VCAM1 and ICAM1, were found to be decreased in responders versus nonresponders, and the authors provided in vitro data in human adipocytes that TNF-β inhibits insulin signaling, GLUT4 mRNA, and insulin-stimulated glucose uptake. These results provide novel insights into the mechanisms via which weight loss promotes enhanced insulin sensitivity, although muscle quantitatively is the major site of insulin resistance.
Reference